Two classes of polyribosomes are present in the cytoplasm of most eukaryotic cells; one bound to the membranes of the endoplasmic reticulum (ER), the other free in the cell sap. Our work has shown that, in addition to their role in the synthesis of secretory proteins, ribosomes attached to the ER membranes play an important role in the synthesis of membrane and organelle proteins. The nature and location of signals within polypeptides and their processing appear to determine whether proteins synthesized on bound polysomes are transferred vectorially into the lumen of the ER or whether they are inserted directly into the membranes at their site of synthesis. Proteins which enter the lumen may be ultimately packaged for secretion or, like beta-glucosidase and cathepsin D may be diverted into lysosomes. Proteins directly inserted into the membranes may be retained in the ER, such as cytochrome P-450 and NADPH cytochrome P-450 reductase or may be transferred to other membrane systems. Some ER membrane proteins such as cytochrome b5 and NADH cytochrome b5 reductase are syntesized on free polysomes and therefore must be released into the cell sap before they are inserted posttranslationally into the membrane. The common site of synthesis of secretory, lysosomal and membrane polypeptides indicates that they contain signals for cotranslational insertion which are functionally equivalent. This suggests the presence of a common receptor in the rough Er membranes. A research for membrane proteins characteristic of rough ER membranes reveals the existence in different animal tissues and species of two transmembrane glycoproteins, which in rat liver have MW 63,000 and 65,000 and have been designated ribophorins I and II respectively. These proteins appear to be related to the binding sites for ribosomes and are absent from smooth membranes. Membrane reconstitution experiments from solubilized microsomal components suggest that, in addition to their role in ribosome binding, ribophorins may also participate in the recognition and processing of signals in nascent polypeptides.